title: Initial human PET studies of metabotropic glutamate receptor type 1 ligand 11C-ITMM.
abstract: N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-(11)C-methoxy-N-methylbenzamide ((11)C-ITMM) is a potential radioligand for mapping metabotropic glutamate receptor type 1 (mGluR1) in the brain by PET. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain imaging of (11)C-ITMM in healthy human subjects.
  
  
  METHODS
  The multiorgan biodistribution and radiation dosimetry of (11)C-ITMM were assessed in 3 healthy human subjects, who underwent 2-h whole-body PET scans. Radiation dosimetry was estimated from the normalized number of disintegrations of source organs using the OLINDA/EXM program. Five healthy human subjects underwent 90-min dynamic (11)C-ITMM scans of brain regions with arterial blood sampling. For anatomic coregistration, T1-weighted MR imaging was performed. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. (11)C-ITMM uptake was assessed quantitatively using a 2-tissue-compartment model.
  
  
  RESULTS
  There were no serious adverse events in any of the subjects throughout the study period. (11)C-ITMM PET demonstrated high uptake in the urinary bladder and gallbladder, indicating both urinary and fecal excretion of radioactivity. The absorbed dose (μGy/MBq) was highest in the urinary bladder wall (13.2 ± 3.5), small intestine (9.8 ± 1.7), and liver (9.1 ± 2.0). The estimated effective dose for (11)C-ITMM was 4.6 ± 0.3 μSv/MBq. (11)C-ITMM showed a gradual increase of radioactivity in the cerebellar cortex. The total distribution volume in the brain regions ranged from 2.61 ± 0.30 (cerebellar cortex) to 0.52 ± 0.17 (pons), and the rank order of the corresponding total distribution volume of (11)C-ITMM was cerebellar cortex > thalamus > frontal cortex > striatum ≈ pons, which was consistent with the known distribution of mGluR1 in the primate brain. The rate of (11)C-ITMM metabolism in plasma was moderate: at 60 min after injection, 62.2% ± 8.2% of the radioactivity in plasma was intact parent compound.
  
  
  CONCLUSIONS
  The initial findings of the present study indicated that (11)C-ITMM PET is feasible for imaging of mGluR1 in the brain. The low effective dose will permit serial examinations in the same subjects.
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. toyohara@pet.tmig.or.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.forename: Muneyuki
authors.initials: M
authors.lastname: Sakata
authors.forename: Keiichi
authors.initials: K
authors.lastname: Oda
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishii
authors.forename: Kimiteru
authors.initials: K
authors.lastname: Ito
authors.forename: Mikio
authors.initials: M
authors.lastname: Hiura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Ming Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
mesh_terms: D000328:Adult; D001549:Benzamides / Q000009:adverse effects / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D006801:Humans; D008024:Ligands; D008297:Male; D049268:Positron-Emission Tomography / Q000009:adverse effects / Q000379:methods*; D011874:Radiometry; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012449:Safety; D013844:Thiazoles / Q000009:adverse effects / Q000378:metabolism*; D051598:Whole Body Imaging; D055815:Young Adult
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; D008024:Ligands; C573292:N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy-N-methylbenzamide; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1
keywords: ITMM; human brain; metabotropic glutamate receptor; radiation dosimetry